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1.
Sci Total Environ ; 792: 148363, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34465051

RESUMO

The alpine meadow in the Qinghai-Tibet Plateau has been seriously degraded due to human activities and climate change in recent decades. Understanding the changes of the soil microbial community in response to the degradation process helps reveal the mechanism underlying the degradation process of alpine meadows. We surveyed and analyzed changes of the vegetation, soil physicochemical properties, and soil microbial community in three degradation levels, namely, non-degradation (ND), moderate degradation (MD), and severe degradation (SD), of the alpine meadows in the northeastern Qinghai-Tibet Plateau. We found that as the level of degradation increased, plant cover, plant density (PD), above-ground biomass (AGB), plant Shannon-Wiener index (PS), soil water content (SWC), soil organic carbon (SOC), total nitrogen (TN), total phosphorus (TP), total potassium (TK), available nitrogen (AN), available phosphorus (AP), and available potassium (AK) decreased significantly, while the soil pH increased from 7.20 to 8.57. Alpine meadow degradation significantly changed the composition of soil bacterial and fungal communities but had no significant impact on the diversity of the microbial communities. Functional predictions indicated that meadow degradation increased the relative abundances of aerobic_chemoheterotrophy, undefined_saprotroph, and plant_pathogen, likely increasing the risk of plant diseases. Redundancy analysis revealed that in ND, the soil microbial community was mainly regulated by PS, PH, PD, SWC, and soil pH. In MD, the soil microbial community was regulated by the soil's available nutrients and SOC. In SD, the soil microbial community was not only regulated by the soil's available nutrients but also influenced by plant characteristics. These results indicate that during alpine meadow degradation, while the changes in the plants and soil environmental factors both affect the composition of the soil microbial community, the influence of soil factors is greater. The soil's available nutrients are the main driving factors regulating the change in the soil microbial community's composition alongside degradation levels.


Assuntos
Microbiota , Solo , Carbono/análise , Pradaria , Humanos , Nutrientes , Microbiologia do Solo , Tibet
2.
Biosens Bioelectron ; 177: 112919, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33515974

RESUMO

Klebsiella pneumoniae is an opportunistic pathogen that is responsible for community acquired infections and nosocomial infections. Antibiotic-resistant K. pneumoniae and/or hypervirulent K. pneumoniae are emerging as a serious threat to public health. For the sake of alleviating and conquering current dilemma, discovery of effective new drugs against K. pneumoniae is a tough challenge. However, traditional anti-K. pneumoniae drug discovery methods cost considerable amount of time, animals, labor and so on. So an efficient technique for in vitro and in vivo drug screening with the least time duration, animals and labor cost is highly needed for the discovery of new effective compounds. Hence, in this study we constructed a selectable marker-free autoluminescent K. pneumoniae (SfAlKp) harboring luxCDABE by combining Tn7 transposon and Xer-dif system. SfAlKp can be used for discovery of new drugs via detecting luminescence intensity as a surrogate marker. The energy-consuming autoluminescent reaction catalyzed by the LuxAB enzymes which use the substrates produced by LuxCDE using the metabolites of the bacteria. Tn7 can insert exogenous genes into the bacterial genome and the DNA fragment in between dif sequences can be recognized and removed by endogenous XerCD recombinases of K. pneumoniae. The drug susceptibility and growth rate of SfAlKp are identical to its parent strain, meanwhile the luminescence intensity and stability are also significant characteristics of SfAlKp. Compared to conventional techniques, the autoluminescence-based measurement is more applicable to high throughput screening for compounds both in vitro as well as in vivo in animal model.


Assuntos
Técnicas Biossensoriais , Infecções por Klebsiella , Preparações Farmacêuticas , Animais , Antibacterianos/farmacologia , Biomarcadores , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae/genética , Camundongos
3.
Biomed Pharmacother ; 131: 110782, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33152940

RESUMO

Multidrug-resistant tuberculosis (MDR-TB) remains a serious public health threat worldwide. To date, the anti-TB activity of TB47 (T), an imidazopyridine amide class of antibiotics targeting QcrB in the electron transport chain, has not been systematically evaluated, especially in a new regimen against MDR-TB. This study employed both macrophage infection and a mouse model to test the activity of T alone or in combination with other antimicrobial agents. Different regimens containing amikacin (A), levofloxacin (L), ethambutol (E), and pyrazinamide (Z) + clofazimine (C)/T were evaluated in the mouse model. The bacterial burdens of mice from different groups were monitored at different time points while relapse was assessed 6 months after treatment cessation. Colonies obtained at relapse underwent drug susceptibility testing. We found that T exhibited highly synergistic bactericidal activity with C in all models. Adding T to ALEZC might shorten the MDR-TB treatment duration from ≥ 9 months to ≤ 5months, as five months of treatment with ALEZCT achieved zero relapse rates in 2 animal experiments. These findings indicate that T exhibits a highly synergistic sterilizing activity when combined with C. All isolates from relapsing mice remained sensitive to each drug, suggesting that the relapse was not due to drug resistance but rather associated with the type of regimen.


Assuntos
Antituberculosos/farmacologia , Clofazimina/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Animais , Antituberculosos/administração & dosagem , Antituberculosos/química , Clofazimina/administração & dosagem , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/isolamento & purificação , Piridinas/administração & dosagem , Piridinas/farmacologia , Recidiva , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia
4.
Infect Dis Poverty ; 9(1): 159, 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33213525

RESUMO

BACKGROUND: Human migration facilitate the spread of tuberculosis (TB). Migrants face an increased risk of TB infection. In this study, we aim to explore the spatial inequity of sputum smear-positive pulmonary TB (SS + PTB) in China; and the spatial heterogeneity between SS + PTB and internal migration. METHODS: Notified SS + PTB cases in 31 provinces in mainland China were obtained from the national web-based PTB surveillance system database. Internal migrant data were extracted from the report on China's migrant population development. Spatial autocorrelations were explored using the global Moran's statistic and local indicators of spatial association. The spatial variation in temporal trends was performed using Kulldorff's scan statistic. Fixed effect and spatial autoregressive models were used to explore the spatial inequity between SS + PTB and internal migration. RESULTS: A total of 2 380 233 SS + PTB cases were reported in China between 2011 and 2017, of which, 1 716 382 (72.11%) were male and 663 851 (27.89%) were female. Over 70% of internal migrants were from rural households and had lower income and less education. The spatial variation in temporal trend results showed that there was an 9.9% average annual decrease in the notification rate of SS + PTB from 2011 to 2017; and spatial clustering of SS + PTB cases was mainly located in western and southern China. The spatial autocorrelation results revealed spatial clustering of internal migration each year (2011-2017), and the clusters were stable within most provinces. Internal emigration, urban-to-rural migration and GDP per capita were significantly associated with SS + PTB, further, internal emigration could explain more variation in SS + PTB in the eastern region in mainland. However, internal immigration and rural-to-urban migration were not significantly associated with SS + PTB across China. CONCLUSIONS: Our study found the spatial inequity between SS + PTB and internal migration. Internal emigration, urban-to-rural migration and GDP per capita were statistically associated with SS + PTB; the negative association was identified between internal emigration, urban-to-rural migration and SS + PTB. Further, we found those migrants with lower income and less education, and most of them were from rural households. These findings can help stakeholders to implement effective PTB control strategies for areas at high risk of PTB and those with high rates of internal migration.


Assuntos
Migrantes/estatística & dados numéricos , Tuberculose Pulmonar/epidemiologia , Adolescente , Adulto , China/epidemiologia , Análise por Conglomerados , Emigração e Imigração/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , População Rural/estatística & dados numéricos , Fatores Socioeconômicos , Análise Espacial , Análise Espaço-Temporal , Escarro/microbiologia , Inquéritos e Questionários , População Urbana/estatística & dados numéricos , Adulto Jovem
5.
Biosens Bioelectron ; 165: 112396, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32729517

RESUMO

Pseudomonas aeruginosa is an increasingly prevalent pathogen that has become a serious health concern due to an increasing incidence of multidrug-resistant (MDR) hospital-acquired infections. The emergence of MDR-P. aeruginosa coupled with shrinking antibiotic pipelines has increased the demand for new antimicrobials and therapeutics. An effective tool for drug screening both in vitro and in vivo can facilitate the discovery of drugs and regimens for treating P. aeruginosa infection. Here, for the first time, we combined the mini-Tn7 system and Xer/dif recombinase system to construct a stable and selectable marker-free autoluminescent P. aeruginosa (SfAlPa) by one step. Afterwards, in vitro and in vivo activities of several antibiotics including amikacin, biapenem, levofloxacin and polymyxin B were assessed using SfAlPa. This study demonstrated that the use of SfAlPa could significantly facilitate rapid real-time evaluating the activities of compounds. Compared to prevailing methods, this method reduces the time, effort, animals and costs consumed in the discovery of new drugs against P. aeruginosa. Additionally, the methodology described in this study could be easily modified for construction of selectable marker-free reporter strain in other Gram-negative bacteria.


Assuntos
Técnicas Biossensoriais , Infecções por Pseudomonas , Animais , Antibacterianos/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Polimixina B , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/genética
6.
Environ Sci Pollut Res Int ; 27(18): 22946-22955, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32328997

RESUMO

The serious ambient fine particulate matter (PM2.5) is one of the key risk factors for lung cancer. However, existing studies on the health effects of PM2.5 in China were less considered the regional transport of PM2.5 concentration. In this study, we aim to explore the association between lung cancer and PM2.5 and then forecast the PM2.5-induced lung cancer morbidity and mortality in China. Ridge regression (RR), partial least squares regression (PLSR), model tree-based (MT) regression, regression tree (RT) approach, and the combined forecasting model (CFM) were alternative forecasting models. The result of the Pearson correlation analysis showed that both local and regional scale PM2.5 concentration had a significant association with lung cancer mortality and morbidity and compared with the local lag and regional lag exposure to ambient PM2.5; the regional lag effect (0.172~0.235 for mortality; 0.146~0.249 for morbidity) was not stronger than the local lag PM2.5 exposure (0.249~0.294 for mortality; 0.215~0.301 for morbidity). The overall forecasting lung cancer morbidity and mortality were 47.63, 47.86, 39.38, and 39.76 per 100,000 population. The spatial distributions of lung cancer morbidity and mortality share a similar spatial pattern in 2015 and 2016, with high lung cancer morbidity and mortality areas mainly located in the central to east coast areas in China. The stakeholders would like to implement a cross-regional PM2.5 control strategy for the areas characterized as a high risk of lung cancer.


Assuntos
Poluentes Atmosféricos/análise , Poluição do Ar/análise , Neoplasias Pulmonares , China , Exposição Ambiental , Humanos , Morbidade , Material Particulado/análise
7.
Infect Dis Poverty ; 9(1): 5, 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32063228

RESUMO

BACKGROUND: Internal migration places individuals at high risk of contracting tuberculosis (TB). However, there is a scarcity of national-level spatial analyses regarding the association between TB and internal migration in China. In our research, we aimed to explore the spatial variation in cases of sputum smear-positive pulmonary TB (SS + PTB) in China; and the associations between SS + PTB, internal migration, socioeconomic factors, and demographic factors in the country between 2005 and 2015. METHODS: Reported cases of SS + PTB were obtained from the national PTB surveillance system database; cases were obtained at the provincial level. Internal migration data were extracted from the national population sampling survey and the census. Spatial autocorrelations were explored using the global Moran's statistic and local indicators of spatial association. The spatial temporal analysis was performed using Kulldorff's scan statistic. Fixed effects regression was used to explore the association between SS + PTB and internal migration. RESULTS: A total of 4 708 563 SS + PTB cases were reported in China between 2005 and 2015, of which 3 376 011 (71.7%) were male and 1 332 552 (28.3%) were female. There was a trend towards decreasing rates of SS + PTB notifications between 2005 and 2015. The result of global spatial autocorrelation indicated that there were significant spatial correlations between SS + PTB rate and internal migration each year (2005-2015). Spatial clustering of SS + PTB cases was mainly located in central and southern China and overlapped with the clusters of emigration. The proportions of emigrants and immigrants were significantly associated with SS + PTB. Per capita GDP and education level were negatively associated with SS + PTB. The internal migration flow maps indicated that migrants preferred neighboring provinces, with most migrating for work or business. CONCLUSIONS: This study found a significant spatial autocorrelation between SS + PTB and internal migration. Both emigration and immigration were statistically associated with SS + PTB, and the association with emigration was stronger than that for immigration. Further, we found that SS + PTB clusters overlapped with emigration clusters, and the internal migration flow maps suggested that migrants from SS + PTB clusters may influence the TB epidemic characteristics of neighboring provinces. These findings can help stakeholders to implement effective PTB control strategies for areas at high risk of PTB and those with high rates of internal migrants.


Assuntos
Escarro/microbiologia , Tuberculose Pulmonar/epidemiologia , Adulto , China/epidemiologia , Análise por Conglomerados , Emigração e Imigração , Feminino , Humanos , Masculino , Fatores Socioeconômicos , Análise Espacial , Análise Espaço-Temporal , Tuberculose Pulmonar/diagnóstico
8.
Microb Drug Resist ; 26(7): 766-775, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31976809

RESUMO

Streptomycin (STR) is the first antibiotic used in the treatment of tuberculosis (TB) and the earliest antituberculosis drug with acquired resistance developed by Mycobacterium tuberculosis. The high prevalence of such resistance in many parts of the world limits its use for treating multidrug-resistant (MDR) TB. The aims of this study are to characterize of mutations in rpsL, rrs, and gidB genes in MDR M. tuberculosis isolates originating from southern China and to investigate possible relationship between mutations and strain genotypes for precise diagnosis and treatment. Sequences of rpsL, rrs, and gidB genes and the resistance profiles were analyzed for 218 MDR M. tuberculosis isolates. Our study showed that 68.35% of MDR M. tuberculosis isolates were resistant to STR and 89.91% of STR-resistant (STRR) isolates were Beijing lineage strains. Mutations were observed in STRR MDR M. tuberculosis isolates at the following rates: 72.48% in rpsL, 36.91% in rrs, and 15.44% in gidB. Compared with the phenotypic data, the combination of mutations in rpsL, rrs, and gidB has sensitivity and specificity of 96.64% and 100.00%, respectively. The most common mutations in STRR isolates were rpsL128,263 and rrs514,1401, of which rpsL128 showed association with Beijing lineage (p < 0.001). It is noteworthy that a1401g mutation was present in rrs, while MDR M. tuberculosis isolates were resistant to both STR and amikacin. Twenty two novel mutations were found in STRR isolates. These findings could be helpful to develop rapid molecular diagnostic methods and understand STR resistance in China for developing TB precision medicine and disturbance of drug-resistant TB transmission.


Assuntos
Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Estreptomicina/farmacologia , Tuberculose Resistente a Múltiplos Medicamentos/genética , China/epidemiologia , Genes Bacterianos , Genótipo , Humanos , Testes de Sensibilidade Microbiana
9.
Medchemcomm ; 10(9): 1635-1640, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31814956

RESUMO

Tuberculosis is the contagious disease responsible for the highest number of deaths worldwide. Here, we screened a commercially available compound library and found napabucasin to possess a moderate anti-tubercular activity against M. tuberculosis H37Ra (MIC 2.5 µg mL-1, 10.4 µM). Three series of napabucasin derivatives were further evaluated for their in vitro anti-tubercular activities against Mtb H37Ra. The activity of most derivatives was either retained or enhanced compared with that of napabucasin. Compound 3s was the most active compound showing a MIC value of 0.3125 µg mL-1 (0.9 µM). Furthermore, several compounds were selected and evaluated against the Mtb H37Rv standard strain and six Mtb clinical isolates. Importantly, these compounds were found to be effective against Mtb clinical isolates with multi-resistance to isoniazid, rifampicin, and ethambutol.

10.
J Microbiol Biotechnol ; 29(9): 1488-1493, 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31387342

RESUMO

The rising cases of multidrug-resistant Acinetobacter baumannii (Ab) and the lack of effective drugs call for quick attention. Here, based on a Tn7 transposon and Xer/dif system, we constructed a stable, selectable marker-free autoluminescent Ab capable of producing visible light without extra substrates. Utilization of this autoluminescent reporter strain has the potential to reduce the time, effort and costs required for the evaluation of activities of anti-Ab drug candidates in vitro.


Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/genética , Antibacterianos/farmacologia , Proteínas Luminescentes/genética , Testes de Sensibilidade Microbiana/métodos , Acinetobacter baumannii/crescimento & desenvolvimento , Proteínas de Bactérias/genética , Contagem de Colônia Microbiana , Elementos de DNA Transponíveis/genética , Farmacorresistência Bacteriana/efeitos dos fármacos , Farmacorresistência Bacteriana/genética , Engenharia Genética , Genoma Bacteriano/genética , Proteínas Luminescentes/metabolismo , Mutagênese Insercional , Deleção de Sequência
11.
Medchemcomm ; 10(1): 49-60, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30774854

RESUMO

Tuberculosis (TB) has become one of the most significant public health problems in recent years. Antibiotic therapy remains the mainstay of TB control strategies, but the increasing resistance of mycobacterial species has heightened alarm, requiring the development of novel drugs in order to improve treatment outcomes. Here, as an effort to identify novel and effective antitubercular agents, we designed and synthesized a series of novel substituted benzimidazolallylidenehydrazinylmethylthiazole derivatives via a multi-component molecular hybridization approach with single molecular architecture. Our design strategy involved assembling the antitubercular pharmacophoric fragments benzimidazole, 2-aminothiazole and substituted α,ß-unsaturated ketones via condensation reactions. All the newly synthesized compounds were fully characterized via NMR and mass spectral data and evaluated for in vitro biological activity against the H37Ra strain of Mycobacterium tuberculosis. From the biological evaluation data, we identified some effective compounds, of which 8g and 7e were the most active ones (both having MIC values of 2.5 µg mL-1). In addition, compound 8g exhibited a lower cytotoxicity profile. We conceive that compound 8g may serve as a chemical probe of interest for further lead optimization studies with the general aim of developing novel and effective antitubercular agents.

12.
Nat Commun ; 10(1): 524, 2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30705268

RESUMO

Buruli ulcer (BU) is an emerging infectious disease that causes disfiguring skin ulcers. The causative agent, Mycobacterium ulcerans, secretes toxin called mycolactone that triggers inflammation and immunopathology. Existing treatments are lengthy and consist of drugs developed for tuberculosis. Here, we report that a pyrazolo[1,5-a]pyridine-3-carboxamide, TB47, is highly bactericidal against M. ulcerans both in vitro and in vivo. In the validated mouse model of BU, TB47 alone reduces M. ulcerans burden in mouse footpads by more than 2.5 log10 CFU compared to the standard BU treatment regimen recommended by the WHO. We show that mutations of ubiquinol-cytochrome C reductase cytochrome subunit B confer resistance to TB47 and the dissimilarity of CydABs from different mycobacteria may account for their differences in susceptibility to TB47. TB47 is highly potent against M. ulcerans and possesses desirable pharmacological attributes and low toxicity that warrant further assessment of this agent for treatment of BU.


Assuntos
Antibacterianos/uso terapêutico , Úlcera de Buruli/tratamento farmacológico , Úlcera de Buruli/microbiologia , Mycobacterium ulcerans/efeitos dos fármacos , Mycobacterium ulcerans/patogenicidade , Animais , Complexo III da Cadeia de Transporte de Elétrons/genética , Camundongos , Mutação , Mycobacterium ulcerans/genética
13.
Arch Pharm (Weinheim) ; 352(4): e1800277, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30698293

RESUMO

A series of novel 3-amidophenols with 5-heteroatomic substitutions were designed and synthesized. Several compounds showed potent antitubercular activity against Mycobacterium tuberculosis H37Ra (MIC = 0.25-5 µg/mL). Compounds 12j and 14i also displayed good inhibitory activity against M. tuberculosis H37Rv and two clinically isolated multidrug-resistant M. tuberculosis strains (MIC = 0.39-3.12 µg/mL). The privileged compound 14i showed certain oral efficacy on a mouse infection model. The compounds are non-cytotoxic against L-O2 hepatocytes and RAW264.7 macrophagocytes. They did not exert inhibitory activity against representative Gram-positive and Gram-negative bacteria.


Assuntos
Amidas/farmacologia , Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Fenóis/farmacologia , Tuberculose/tratamento farmacológico , Administração Oral , Amidas/síntese química , Amidas/química , Animais , Antituberculosos/síntese química , Antituberculosos/química , Linhagem Celular , Farmacorresistência Bacteriana Múltipla , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Fenóis/síntese química , Fenóis/química , Células RAW 264.7 , Relação Estrutura-Atividade , Tuberculose/microbiologia
14.
Chem Pharm Bull (Tokyo) ; 67(4): 372-381, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30686792

RESUMO

A series of meta-amido bromophenol derivatives were designed and synthesized. The compounds were found to potently inhibit the growth of Mycobacterium tuberculosis H37Ra. They also exhibited moderate inhibitory activity against Mycobacterium tuberculosis H37Rv and multidrug-resistant strains. The compounds did not show inhibitory activity against normal Gram-positive and Gram-negative bacteria. Moderate cytotoxicities and good metabolic stability were observed for the selected compounds. The results demonstrated meta-amido bromophenols as a new class of antitubercular agents with good potentials.


Assuntos
Antituberculosos/química , Fenóis/química , Desenho de Fármacos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Fenóis/farmacologia , Relação Estrutura-Atividade
15.
J Thorac Dis ; 11(11): 4613-4625, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31903250

RESUMO

Background: Levofloxacin (LVX) and Moxifloxacin (MXF) are the cornerstones for treatment of multidrug-resistant tuberculosis (MDR-TB). China is one of the highest MDR- and fluoroquinolones (FQ)-resistant TB burdens countries. DNA gyrase encoded by gyr genes is the main target of FQ in Mycobacterium tuberculosis (MTB). The prevalence and molecular characterization of LVX- and MXF-resistant MTB strains from southern China were examined in this study. Methods: Drug susceptibility testing (DST) of 400 MTB clinical isolates was evaluated by proportion method on Löwenstein-Jensen (LJ) medium against ten drugs. The sequencing of entire gyrA and gyrB genes and multiplex PCR were performed to distinguish the prevalence of mutant types in Beijing and non-Beijing genotypes. Results: Three hundred and twenty-one out of four hundred (80.25%) drug-resistant isolates (resistant > one drug) were categorized as 83/321 (25.80%) MDR, 174/321 (54.20%) pre-XDR and 64/321 (19.93%) XDR-MTB. Overall, 303/400 (75.75%) LVX- and 292/400 (73.00%) MXF-resistant (R) MTB strains were identified. Two hundred seventy-one out of three hundred and three (89.43%) resistant strains carried mutations in gyrA and 91/303 (30.03%) in gyrB. Interestingly, 18 novel mutations were detected in gyrA and gyrB genes. Mutations at (A90, D94) and (T500, G510, G512) frequently existed in QRDR(s) of gyrA and gyrB respectively in 286/400 (71.50%) LVXRMXFR strains. The novel mutations in- and out-side the QRDR of gyrA (L105R, A126E, M127K, D151T, V165A) and gyrB (D461H, N499S, G520A) increased the sensitivity and consistency of genotypic tests. Notably, 25 LVXRMXFR strains were found with unknown resistance mechanisms. Conclusions: Mutations in QRDR(s) were concomitantly associated with Beijing and non-Beijing genotypes. The prevalence of resistance and cross-resistance between LVX and MXF in MTB isolates from southern China was immensely higher than other countries. Our valuable findings provide the substantial implications to improve the reliability of genotypic diagnostic tests relying on potential resistance conferring mutations in entire gyr genes.

16.
Medchemcomm ; 9(8): 1293-1304, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30151083

RESUMO

A series of m-amidophenol derivatives (6a-6l, 7a-7q, 9a, 9b, 12a-12c, 14 and 15) were designed and synthesized. Their antitubercular activities were evaluated in vitro against M. tuberculosis strains H37Ra and H37Rv and clinically isolated multidrug-resistant M. tuberculosis strains. Ten compounds displayed minimal inhibitory concentrations (MICs) against M. tuberculosis H37Ra below 2.5 µg mL-1 and 6g was the most active compound (MIC = 0.625 µg mL-1). Compounds 6g and 7a also showed potent inhibitory activity against M. tuberculosis H37Rv (MIC = 0.39 µg mL-1) and several clinically isolated multidrug-resistant M. tuberculosis strains (MIC = 0.39-3.125 µg mL-1). The compounds did not show inhibitory activity against normal Gram-positive and Gram-negative bacteria. They exhibited low cytotoxicity against HepG2 and RAW264.7 cell lines. The results demonstrated m-amidophenol as an attractive scaffold for the development of new antitubercular agents.

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